A fetal-adult hybrid of troponin I created through genetic engineering improves cardiac function in mice with damaged hearts and human myocytes taken from hearts of cardiac transplant recipients, according to an article published online January 22nd by Nature Medicine.

The key was using genetic engineering technology to replace one alanine found in the adult form of troponin I with a histidine (representing the fetal form of the same protein).

“The most important finding of our study was that this modified troponin I protein dramatically improved heart function under a variety of conditions associated with cardiovascular damage and heart failure,” said Sharlene Day, MD, lead author of the paper.

“This study provides the first evidence that a single histidine substitution in troponin I can improve short- and long-term cardiac function in laboratory mice with heart failure,” said Joseph M. Metzger, PhD, a coauthor. “The fact that we also were able to rescue the functionality of damaged human heart cells is a significant advance.”

During embryonic development, the fetal form of the protein makes the myocardium more resistant than adult myocardium to effects of acidosis and low oxygen, meaning that fetal hearts largely retain the ability to respond to calcium under adverse conditions.

“Shortly before or after birth, the gene for fetal troponin I is turned off and the adult gene is turned on,” said Margaret Westfall, PhD, another coauthor. “Although the adult form of troponin I is more susceptible to the harmful effects of acidosis, it has other important properties that enable the adult heart to respond to hormones during exercise and periods of stress.”

In essence, the researchers created a genetic hybrid of troponin I to combine the advantages of the fetal and adult form of the protein. According to the researchers, the modified protein helps the heart respond to a harsh intracellular environment by boosting its performance during periods of stress.

In experiments with isolated myocytes, a virus delivered the modified troponin I gene. When cells were analyzed for expression of troponin I with the histidine substitution, researchers discovered that “you don’t need 100 percent gene replacement to see a biological effect in individual myofilaments. We see favorable effects at 20 percent to 50 percent replacement.”

To create the damaging conditions associated with an interruption in blood supply, Day ligated a coronary artery in mice. Hearts from transgenic mice performed far better after the procedure than hearts from mice without modified troponin I.
The research team also found that hearts from transgenic mice contracted more efficiently and used less energy to perform more work than hearts from non-transgenic littermates.

The team is studying the effects of the genetically engineered troponin I protein in other research animals and exploring mechanisms responsible for its cardioprotective effect. They believe the modified troponin I protein senses changes within cardiac muscle cells and responds by improving the cells’ ability to contract efficiently in response to stress.